Human immunodeficiency virus (HIV) replicates in brain microglia and is known to cause behavioral and cognitive dysfunctions in patients with AIDS. Observations of isolation of HIV from seronegative individuals and synthesis of HIV-specific IgG antibodies in the brain suggest that infection of brain with HIV may occur very early in the course of AIDS dementia complex (ADC). The role of the neuropeptide in the production of cytokine or HIV-induced neuronal denegration has not been investigated. Therefore it is important to determine whether the neuropeptides have any effect on the production of cytokines as well as on neuronal degeneration. Preliminary work has been done on one-day-old rat mixed brain cell cultures. Treatment of mixed brain cell cultures with LPS (50 5 g/ml) caused the death of tyrosine hydroxylase- positive neurons (~ 50%) and choline acetyltranferese-positive neurons (~35%), while LPS caused the death of the rest of the neurons to a lesser degree. Pretreatment with the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (NAME, 0.5 mM) protected the cholinergic neurons. Inducible NOS is visible is microglia in these cultures two days after LPS treatment, as are high levels of the nitric oxide metabolite nitrite. In addition to NAME, a number of drugs including anti-inflammatory steroid dexamthasone and the opiate morphine inhibit the accumulation of nitrite, and presumably inhibit the formation of neurotoxic levels of nitric oxide in these cultures in response to LPS. Moreover, ME (10-6 M) and morphine (10-10 M), an opiate alkaloid, protect tyrosine hydroxylase positive-neuron from LPS-induced death.